Leveraging Genetics to Improve Cardiovascular Health in Diabetes: The 2018 Edwin Bierman Award Lecture

Abstract

The past decade has witnessed an exponential increase in our ability to search the genome for genetic factors predisposing to cardiovascular disease (CVD) and in particular coronary heart disease (CHD). Identifying these genes could lead to the development of innovative strategies to prevent the cardiovascular complications of diabetes by allowing us to 1 ) create predictive algorithms for the identification of patients at especially high risk of CVD so that these individuals can undergo preventive interventions early in the natural history of the disease; 2 ) discover as yet unknown disease pathways linking diabetes to atherosclerosis, which can be used as targets for the development of new CVD-preventing drugs specifically directed at subjects with diabetes; and 3 ) devise personalized programs increasing the cost-effectiveness of preventive interventions by tailoring them to the genetic background of each patient. Substantial progress has been made in each of these three areas as exemplified by the recent development of a CHD genetic risk score improving CHD prediction among subjects with type 2 diabetes, the discovery of a diabetes-specific CHD locus on 1q25 pointing to glutamine synthase ( GLUL ) and the γ-glutamyl cycle as key regulators of CHD risk in diabetes, and the identification of two genetic loci allowing the selection of patients with type 2 diabetes who may especially benefit from intensive glycemic control. Translating these discoveries into clinical practice will not be without challenges, but the potential rewards, from the perspective of public health as well as that of persons with diabetes, make this goal worth pursuing.

The Liability Threshold Model for Predicting the Risk of Cardiovascular Disease in Patients with Type 2 Diabetes: A Multi-Cohort Study of Korean Adults

“…In this LMM-based genetic association study, four SNPs, rs4538911, rs7946015, rs17465734, and rs9982069, did not achieve a genome-wide threshold of p < 5 × 10 −8 but exhibited suggestive associations with DCVD risk (5 × 10 −7 < p < 1 × 10 −5 ). The SNP, rs10911021, located near the GLUL gene (1q25), which had been associated with CHD in Caucasian T2D patients, revealed no significant association in this East Asian study [ 6 , 18 ]. On the other hand, we found significant associations between DCVD and 15 reported SNPs located in or near CVD candidate genes, including CELSR2-PSRC1 , CDKN2B , TFCP2L1 , HDAC4 , MRAS , SPSB4 , KCNN2 , MYL2 , and ZFHX3 (0.001 < p < 0.05) [ 5 , 19 ].…”

Association of metabolic syndrome components with circulating levels of cytokine clusters in young women

“…Insulin resistance (IR) is the pathophysiological basis of metabolic diseases, such as type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS) and nonalcoholic fatty liver disease (NAFLD) [1][2][3][4]. Increased IR in T2DM patients, obesity and MetS individuals is a high-risk factor for cardiovascular disease (CVD) [5][6]. MetS is a group of metabolic abnormalities related to IR, T2DM and CVD [7][8].…”

Association of the 1q25 Diabetes-Specific Coronary Heart Disease Locus With Alterations of the γ-Glutamyl Cycle and Increased Methylglyoxal Levels in Endothelial Cells

“…In order to change the status quo, new interventions are needed that specifically target the mechanisms linking the diabetic milieu to vascular damage. Our strategy to gain insights into these mechanisms and identify novel targets for preventive therapies has been to study the genetic factors that modulate cardiovascular risk among people with type 2 diabetes (2).…”